Zhao Xiao-Yun, Ling Yi-Ling, Li Yu-Guang, Meng Ai-Hong, Xing Han-Ying
The First Affiliated Hospital of Shantou University Medical College, Shantou 515031, Guangdong Province, China.
World J Gastroenterol. 2005 Jun 14;11(22):3405-10. doi: 10.3748/wjg.v11.i22.3405.
To explore the effect of sulfated cholecystokinin octapeptide (sCCK-8) on cardiac functions and its receptor mechanism in endotoxic shock (ES) rats.
The changes of the mean arterial pressure (MAP), heart rate (HR), the left ventricular pressure (LVP) and the maximal/minimum rate of LVP (+/-LVdp/dt(max))) were measured by using physiological record instrument in eight groups of rats. The expression of cholecystokinin-A receptor (CCK-AR) and cholecystokinin-B receptor (CCK-BR) mRNA of myocardium in ES rats was examined by reverse transcription polymerase chain reaction (RT-PCR).
(1) Low doses of sCCK-8 (0.4 microg/kg) caused tachycardia (441+/-27, normal control 391+/-22 s/min) and slight increase in MAP, LVP and +/-LVdp/dt(max) (16.96+/-1.79, 18.21+/-1.69 and +768.85+/-31.28/-565.04+/-27.71 kPa, respectively, all P<0.01), while medium doses (4.0 microg/kg) and high doses of sCCK-8 (40 microg/kg) elicited bradycardia and marked increase in MAP, LVP and +/-LVdp/dt(max) (17.29+/-1.63, 19.46+/-2.57 and +831.46+/-22.57/-606.08 +/-31.32; 17.46+/-1.08, 19.83+/-2.91 and +914.52+/-35.95/-639.15+/-30.23 kPa, respectively, all P<0.01). Proglumide (1.0 mg/kg), a nonselective antagonist of CCK-receptor (CCK-R), significantly inhibited the pressor effects of sCCK-8 (15.96+/-1.38, 17.36+/-0.66 and +748.18+/-19.29/-512.12+/-14.39 kPa, respectively, all P<0.01), whilst reversing the bradycardiac responses. (2) High doses of LPS (8 mg/kg) elicited marked decrease in MAP, LVP and +/-LVdp/dt(max). (7.16+/-0.59, 7.6+/-0.68 and +298.01+/-25.52/-166.96+/-19.25 kPa, respectively, all P<0.01). Pretreatment with sCCK-8 (40 microg/kg) could reverse the decline of cardiac functions (10.71+/-0.45, 11.7+/-1.26 and +446.04+/-67.18/-347.90+/-36.98 kPa, respectively, all P<0.01), while proglumide could cause further decline of cardiac function in ES rats (4.71+/-0.67, 5.58+/-1.25 and +226.48+/-15.84/-142.83+/-20.23 kPa, respectively, all P<0.01). (3) CCK-A/BR mRNAs were expressed in myocardium of control rats. Gene expression of CCK-AR and CCK-BR significantly increased in myocardium of ES rats. The increase of CCK-AR mRNA induced by LPS began at 0.5 h, peaked at 2 h, kept a high level at 6 h and declined at 12 h, respectively. Similar to CCK-AR mRNA, the expression of CCK-BR mRNA peaked at 2 h and kept a high level at 6 h, but it did not change at the first 0.5 h and was stable at a high level at 12 h.
The above results indicate that endogenous and exogenous sCCK-8 may significantly improve cardiac function and intractable hypotension of ES rats, which was likely related to high expression of CCK-A/BR in myocardium induced by LPS.
探讨硫酸化胆囊收缩素八肽（sCCK - 8）对内毒素休克（ES）大鼠心功能的影响及其受体机制。
用生理记录仪测定八组大鼠的平均动脉压（MAP）、心率（HR）、左心室压力（LVP）和左心室压力最大/最小变化率（+/-LVdp/dt(max)）。采用逆转录聚合酶链反应（RT - PCR）检测ES大鼠心肌中胆囊收缩素A受体（CCK - AR）和胆囊收缩素B受体（CCK - BR）mRNA的表达。
（1）低剂量sCCK - 8（0.4μg/kg）引起心动过速（441±27，正常对照391±22次/分钟），MAP、LVP和+/-LVdp/dt(max)轻度升高（分别为16.96±1.79、18.21±1.69和+768.85±31.28/-565.04±27.71kPa，均P<0.01），而中剂量（4.0μg/kg）和高剂量sCCK - 8（40μg/kg）引起心动过缓，MAP、LVP和+/-LVdp/dt(max)显著升高（分别为17.29±1.63、19.46±2.57和+831.46±22.57/-606.08±31.32；17.46±1.08、19.83±2.91和+914.52±35.95/-639.15±30.23kPa，均P<0.01）。CCK受体（CCK - R）的非选择性拮抗剂丙谷胺（1.0mg/kg）显著抑制sCCK - 8的升压作用（分别为15.96±1.38、17.36±0.66和+748.18±19.29/-512.12±14.39kPa，均P<0.01），同时逆转心动过缓反应。（2）高剂量脂多糖（LPS，8mg/kg）引起MAP、LVP和+/-LVdp/dt(max)显著降低（分别为7.16±0.59、7.6±0.68和+298.01±25.52/-166.96±19.25kPa，均P<0.01）。sCCK - 8（40μg/kg）预处理可逆转心功能下降（分别为10.71±0.45、11.7±1.26和+446.04±67.18/-347.90±36.98kPa，均P<0.01），而丙谷胺可使ES大鼠心功能进一步下降（分别为4.71±0.67、5.58±1.25和+226.48±15.84/-142.83±20.23kPa，均P<0.01）。（3）CCK - A/BR mRNAs在对照大鼠心肌中表达。ES大鼠心肌中CCK - AR和CCK - BR的基因表达显著增加。LPS诱导的CCK - AR mRNA增加始于0.5小时，2小时达到峰值，6小时保持高水平，12小时下降。与CCK - AR mRNA相似，CCK - BR mRNA的表达在2小时达到峰值，6小时保持高水平，但在最初0.5小时没有变化，12小时稳定在高水平。
上述结果表明，内源性和外源性sCCK - 8可能显著改善ES大鼠的心功能和顽固性低血压，这可能与LPS诱导心肌中CCK - A/BR的高表达有关。
